Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy.

Holly J Garringer,Barry B Muhoberac,Ruben Vidal,Rebecca J Chan,Wei Li,Anthony Acton,Munro Peacock,Charles B Goodwin,Bernardino Ghetti,Jose M Irimia,Briana Richine

doi:10.1371/journal.pone.0161341

Holly J Garringer, Barry B Muhoberac + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0161341

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Journal: PloS one	Publication Date: Aug 30, 2016
Citations: 24	License type: CC BY 4.0

Affiliation: Indiana University – Purdue University Indianapolis

Abstract

Mutations in the ferritin light chain (FTL) gene cause the neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies (IBs) in glia and neurons throughout the central nervous system (CNS) and in tissues of multiple organ systems. Herein, using primary mouse embryonic fibroblasts from a mouse model of HF, we show significant intracellular accumulation of ferritin and an increase in susceptibility to oxidative damage when cells are exposed to iron. Treatment of the cells with the iron chelator deferiprone (DFP) led to a significant improvement in cell viability and a decrease in iron content. In vivo, iron overload and DFP treatment of the mouse model had remarkable effects on systemic iron homeostasis and ferritin deposition, without significantly affecting CNS pathology. Our study highlights the role of iron in modulating ferritin aggregation in vivo in the disease HF. It also puts emphasis on the potential usefulness of a therapy based on chelators that can target the CNS to remove and redistribute iron and to resolubilize or prevent ferritin aggregation while maintaining normal systemic iron stores.

Highlights

Neuroferritinopathy or hereditary ferritinopathy (HF) is an autosomal dominant movement disorder caused by mutations in the ferritin light chain (FTL) gene on chromosome 19q13.3
Lm was detected in the stacking gel (St) of iron-loaded immortalized MEF (iMEF) from FTL-Tg mice, suggesting the formation of SDS-resistant aggregates, as we previously described [10]
Dysregulation of iron metabolism has been well-documented in neurodegenerative diseases, in particular in the disease HF, in which abnormal iron metabolism plays a primary role in the pathogenesis of the disease [1]

Summary

Introduction

Neuroferritinopathy or hereditary ferritinopathy (HF) is an autosomal dominant movement disorder caused by mutations in the ferritin light chain (FTL) gene on chromosome 19q13.3. All mutations occur in exon 4 of the FTL gene, leading to the generation of a ferritin light (L) subunit with a longer than normal C-terminal sequence with disordered structure [1]. The main pathologic findings in HF are cystic cavitation of the basal ganglia, the presence of intranuclear and intracytoplasmic ferritin inclusion bodies (IBs) in glial cells and neurons in the central nervous system (CNS), and substantial iron deposition. Mutation carriers may present various systemic diseases before the onset of the CNS disease, but it remains to be determined whether these diseases are associated with the presence of IBs in tissues of multiple organ systems outside the CNS [3]. The presence of IBs in skin and muscle may be useful for the diagnosis of the disease by a biopsy and to monitor the efficacy of therapeutic approaches [4]

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